Glucopyranosyl-substituted difluorobenzyl-benzene derivates, medicaments containing such compounds, their use and process for their manufacture

ABSTRACT

Glucopyranosyl-substituted difluorobenzyl-benzene derivatives of general formula (I) as defined according to claim 1, including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

AIM OF THE INVENTION

The aim of the present invention is to find new pyranosyl-substitutedbenzene derivatives, particularly those which are active with regard tothe sodium-dependent glucose cotransporter SGLT, particularly SGLT2. Afurther aim of the present invention is to discoverpyranosyl-substituted benzene derivatives which have a good to very goodinhibitory effect on the sodium-dependent glucose cotransporter SGLT2 invitro and/or in vivo and/or have good to very good pharmacologicaland/or pharmacokinetic and/or physicochemical properties.

A further aim of the present invention is to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofmetabolic disorders, particularly diabetes.

The invention also sets out to provide a process for preparing thecompounds according to the invention.

Other aims of the present invention will become apparent to the skilledman directly from the foregoing and following remarks.

OBJECT OF THE INVENTION

In a first aspect the present invention relates toglucopyranosyl-substituted difluorobenzyl-benzene derivatives of generalformula I

wherein

-   R¹ denotes hydrogen, fluorine, chlorine, bromine, iodine,    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy,    C₃₋₇-cycloalkyloxy, C₅₋₇-cycloalkenyloxy, C₁₋₄-alkylsulfanyl, amino,    nitro or cyano,    -   while the above-mentioned alkyl-, alkenyl-, alkynyl-,        cycloalkyl- und cycloalkenyl-residues may be mono- or        polysubstituted by fluorine and/or mono- or disubstituted by        identical or different substituents L2, and    -   while in the above-mentioned C₅₋₆-cycloalkyl and        C₅₋₆-cycloalkenyl rings one or two methylene groups may be        replaced independently of one another by O, S, CO, SO or SO₂,        and-   R² denotes hydrogen, fluorine, chlorine, bromine, hydroxy,    C₁₋₄-alkyl, C₁₋₄-alkoxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy or    cyano, while the alkyl or alkoxy group may be mono- or    polysubstituted by fluorine, and-   R³ hydrogen, fluorine, chlorine, bromine, iodine, C₁₋₆-alkyl,    C₂₋₆-alkynyl, C₂₋₆-alkenyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₅₋₇-cycloalkenyl,    C₅₋₇-cycloalkenyl-C₁₋₃-alkyl, aryl, heteroaryl, C₁₋₄-alkylcarbonyl,    arylcarbonyl, heteroarylcarbonyl, aminocarbonyl,    C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)aminocarbonyl,    pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,    morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl,    4-(C₁₋₄-alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl,    C₁₋₄-alkoxycarbonyl, C₁₋₄-alkylamino, di-(C₁₋₃-alkyl)amino,    pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl,    4-(C₁₋₄-alkyl)piperazin-1-yl, C₁₋₄-alkylcarbonylamino,    arylcarbonylamino, heteroarylcarbonylamino, C₁₋₄-alkylsulfonylamino,    arylsulfonylamino, C₁₋₆-alkoxy, C₃₋₇-cycloalkyloxy,    C₅₋₇-cycloalkenyloxy, aryloxy, heteroaryloxy, C₁₋₄-alkylsulfanyl,    C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl, C₃₋₇-cycloalkylsulfanyl,    C₃₋₇-cycloalkylsulfinyl, C₃₋₇-cycloalkylsulfonyl,    C₅₋₇-cycloalkenylsulfanyl, C₅₋₇-cycloalkenylsulfinyl,    C₅₋₇-cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl,    heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, amino,    hydroxy, cyano and nitro,    -   while the above-mentioned alkyl-, alkenyl-, alkynyl-,        cycloalkyl- und cycloalkenyl-residues may be mono- or        polysubstituted by fluorine and/or mono- or disubstituted by        identical or different substituents L2, and    -   while in the above-mentioned C₅₋₆-cycloalkyl and        C₅₋₆-cycloalkenyl rings one or two methylene groups may be        replaced independently of one another by O, S, CO, SO or SO₂,        and    -   while in the above-mentioned N-heterocycloalkyl rings one        methylene group may be replaced by CO or SO₂, and-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, iodine, hydroxy, cyano, C₁₋₃-alkyl,    difluoromethyl, trifluoromethyl, C₁₋₃-alkoxy, difluoromethoxy,    trifluoromethoxy, amino, C₁₋₃-alkyl-amino and di(C₁₋₃-alkyl)-amino;    and-   L2 independently of one another are selected from among fluorine,    chlorine, hydroxy, hydroxyl-C₁₋₄-alkyl, C₁₋₄-alkoxy,    trifluoromethoxy, C₁₋₄-alkoxy-C₁₋₄-alkyl, cyano, hydroxycarbonyl,    (C₁₋₄-alkyl)oxycarbonyl, aminocarbonyl, C₁₋₄-alkyl, trifluoromethyl,    amino, C₁₋₄-alkyl-carbonylamino, C₁₋₃-alkyl-amino and    di(C₁₋₃-alkyl)-amino; and-   R⁶, R^(7a)-   R^(7b), R^(7c) independently of one another have a meaning selected    from among hydrogen, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl, while the aryl-groups may be mono- or    disubstituted independently of one another by identical or different    groups L1;    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups which may be substituted    as defined; and    while, unless otherwise stated, the above-mentioned alkyl groups may    be straight-chain or branched,    the tautomers, the stereoisomers thereof, the mixtures thereof and    the salts thereof.

The compounds of general formula I according to the invention and thephysiologically acceptable salts thereof have valuable pharmacologicalproperties, particularly an inhibitory effect on the sodium-dependentglucose cotransporter SGLT, particularly SGLT2. Moreover compoundsaccording to the invention may have an inhibitory effect on thesodium-dependent glucose cotransporter SGLT1. Compared with a possibleinhibitory effect on SGLT1 the compounds according to the inventionpreferably inhibit SGLT2 selectively.

The present invention also relates to the physiologically acceptablesalts of the compounds according to the invention with inorganic ororganic acids.

This invention also relates to pharmaceutical compositions, containingat least one compound according to the invention or a physiologicallyacceptable salt according to the invention, optionally together with oneor more inert carriers and/or diluents.

This invention also relates to the use of at least one compoundaccording to the invention or one of the physiologically acceptablesalts thereof for preparing a pharmaceutical composition which issuitable for the treatment or prevention of diseases or conditions whichcan be influenced by inhibiting the sodium-dependent glucosecotransporter SGLT, particularly SGLT2.

This invention also relates to the use of at least one compoundaccording to the invention or one of the physiologically acceptablesalts thereof for preparing a pharmaceutical composition which issuitable for the treatment of metabolic disorders.

In a further aspect the present invention relates to the use of at leastone compound according to the invention or one of the physiologicallyacceptable salts thereof for preparing a pharmaceutical composition forpreventing the degeneration of pancreatic beta cells and/or forimproving and/or restoring the functionality of pancreatic beta cells.

In a further aspect the present invention relates to a use of at leastone compound according to the invention or one of the physiologicallyacceptable salts thereof for preparing a pharmaceutical composition forpreventing, slowing, delaying or treating diseases or conditionsattributed to an abnormal accumulation of liver fat in a patient in needthereof.

This invention also relates to the use of at least one compoundaccording to the invention or one of the physiologically acceptablesalts thereof for preparing a pharmaceutical composition for inhibitingthe sodium-dependent glucose cotransporter SGLT, particularly SGLT2.

The invention further relates to a process for preparing apharmaceutical composition according to the invention, characterised inthat a compound according to the invention or one of the physiologicallyacceptable salts thereof is incorporated in one or more inert carriersand/or diluents by a non-chemical method.

The present invention also relates to a process for preparing thecompounds of general formula I according to the invention, characterisedin that

a) in order to prepare compounds of general formula I which are definedas hereinbefore and hereinafter,a compound of general formula II

wherein

-   R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be    mono- or polysubstituted by halogen;-   R^(8a), R^(8b),-   R^(8c), R^(8d) independently of one another have one of the meanings    given hereinbefore and hereinafter for the groups R⁶, R⁷, R^(7b),    R^(7c), or denote a benzyl or allyl group or a R^(a)R^(b)R^(c)Si    group or a ketal or acetal group, particularly an alkylidene or    arylalkylidene ketal or acetal group, while in each case two    adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclic    silyl ketal, ketal or acetal group or a    1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge, while the    above-mentioned ethylene bridge forms, together with two oxygen    atoms and the two associated carbon atoms of the pyranose ring, a    substituted dioxane ring, particularly a    2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and while alkyl,    aryl and/or benzyl groups may be mono- or polysubstituted by halogen    or C₁₋₃-alkoxy, and while benzyl groups may also be substituted by a    di-(C₁₋₃-alkyl)amino group; and-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, wherein the aryl or alkyl groups may be    mono- or polysubstituted by halogen;    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups;    and wherein the groups R¹ to R³ and R⁶, R^(7a), R^(7b), R^(7c) are    defined as hereinbefore and hereinafter;    is reacted with a reducing agent in the presence of a Lewis or    Brønsted acid, while any protective groups present are cleaved    simultaneously or subsequently; or    b) in order to prepare compounds of general formula I wherein R⁶,    R^(7a), R^(7b) and R^(7c) denote hydrogen,    a compound of general formula III

wherein R^(8a), R^(8b), R^(8c), R^(8d) and R¹ to R³ are defined ashereinbefore and hereinafter, but at least one of the groups R^(8a),R^(8b), R^(8c), R^(8d) does not denote hydrogen, is hydrolysed, andif desired a compound of general formula I thus obtained wherein R⁶denotes a hydrogen atom, is converted by acylation into a correspondingacyl compound of general formula I, and/orif necessary any protective group used in the reactions described aboveis cleaved and/orif desired a compound of general formula I thus obtained is resolvedinto its stereoisomers and/orif desired a compound of general formula I thus obtained is convertedinto the salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts thereof.

This invention further relates to a process for preparing compounds ofgeneral formula II

wherein

-   R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be    mono- or polysubstituted by halogen;-   R^(8a), R^(8b),-   R^(8c), R^(8d) independently of one another has one of the meanings    given for the groups R⁶, R^(7a), R^(7b), R^(7c), or denote a benzyl    or allyl group or a R^(a)R^(b)R^(c)Si group or a ketal or acetal    group, while in each case two adjacent groups R^(8a), R^(8b)b,    R^(8c), R^(8d) may form a cyclic silyl ketal, ketal or acetal group    or may form, with two oxygen atoms of the pyranose ring, a    substituted 2,3-oxydioxane ring, particularly a    2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and while alkyl,    aryl and/or benzyl groups may be mono- or polysubstituted by halogen    or C₁₋₃-alkoxy, and while benzyl groups may also be substituted by a    di-(C₁₋₃-alkyl)amino group; and-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl or aryl groups may be mono-    or polysubstituted by halogen;    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups;    and R¹ to R³, R⁶, R^(7a), R^(7b), R^(7c) are defined as hereinbefore    and hereinafter,    wherein an organometallic compound (V) which may be obtained by    halogen-metal exchange or by inserting a metal in the carbon-halogen    bond of a halogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R¹ to R³ are defined ashereinbefore and hereinafter, and optionally subsequenttransmetallation, is added to a gluconolactone of general formula VI

wherein R^(8a), R^(8b), R^(8c), R^(8d) are defined as hereinbefore andhereinafter, andthen the resulting adduct is reacted with water or an alcohol R′—OH,while R′ denotes optionally substituted C₁₋₄-alkyl, in the presence ofan acid, such as for example methanesulfonic acid, sulfuric acid,hydrochloric acid, acetic acid or ammonium chloride, and optionally theproduct obtained in the reaction with water wherein R′ denotes H isconverted, in a subsequent reaction, with an alcohol in the presence ofan acid to yield the alkoxy derivative or with an acylating agent, suchas for example the corresponding acid chloride or anhydride, into theproduct of formula II wherein R′ denotes (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl or aryl-(C₁₋₃-alkyl)-carbonyl,which may be substituted as specified.

The intermediate products listed, particularly those of formula IV,formula II and formula III, are also a subject of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly R¹ to R³, L1, L2, R⁶, R^(7a), R^(7b), R^(7c), R^(8a),R^(8b), R^(8c), R^(8d), are defined as above and hereinafter.

If residues, substituents or groups occur several times in a compound,as for example L1 and L2, they may have the same or different meanings.

Some preferred meanings of individual groups and substituents of thecompounds according to the invention will be given hereinafter.

Preferred compounds according to the present invention can be describedby the formulae I.1 to I.4:

The two fluorine atoms at the benzyl group which also bears thesubstituent R³ are preferably located at C-2 and C-6 or C-2 and C-3relative to the —CH₂-bridge. Therefore compounds according to theformulae I.1 and I.2 are particularly preferred.

The group R¹ preferably denotes fluorine, chlorine, bromine, cyano,C₁₋₄-alkyl, C₁₋₄-alkyloxy, C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyloxy, whilein a C₅₋₆-cycloalkyl ring a methylene group may be replaced by O, andwherein any alkyl group or cycloalkyl ring may be mono- orpoly-fluorinated and/or mono- or disubstituted with identical ordifferent substituents L2.

Particularly preferred meanings of R¹ are chlorine, bromine, methyl,ethyl, cyano, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl;particularly methyl, cyano and chlorine.

Preferred meanings of the group R² are hydrogen, fluorine, chlorine,methyl, methoxy, ethoxy and methyl substituted by 1 to 3 fluorine atoms.

Particularly preferred meanings of the group R² are hydrogen, fluorine,methoxy, ethoxy and methyl, particularly hydrogen.

Preferred meanings of the group R³ are chlorine, bromine, iodine,C₁₋₄-alkyl, C₃₋₇-cycloalkyl, hydroxyl, C₁₋₄-alkyloxy,C₃₋₇-cycloalkyloxy, C₁₋₄-alkylsulfanyl, C₃₋₇-cycloalkylsulfanyl, whilein a C₅₋₆-cycloalkyl ring a methylene group may be replaced by O, andwherein any alkyl group and cycloalkyl ring may be mono- orpolyfluorinated and/or mono- or disubstituted with identical ordifferent substituents L2. In particular chlorine, bromine, methyl,ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, difluoromethyl, trifluoromethyl, 2-hydroxyl-ethyl,hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, difluoromethoxy,trifluoromethoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy,(S)-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, methylsulfanyl and ethylsulfanyl; moreparticularly methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy,ethoxy, isopropoxy, methylsulfanyl and ethylsulfanyl.

Preferred meanings of the group L1 independently of one another areselected from among fluorine, chlorine, bromine, cyano, hydroxy,C₁₋₃-alkyl, difluoromethyl, trifluoromethyl, C₁₋₃-alkoxy,difluoromethoxy, trifluoromethoxy and di(C₁₋₃-alkyl)-amino.

Particularly preferred meanings of the group L1 are selected fromfluorine, chlorine, hydroxy, trifluoromethyl, ethyl, methoxy, ethoxy anddimethylamino, particularly methyl, ethyl, methoxy, ethoxy anddimethylamino.

Preferred meanings of the group L2 independently of one another areselected from among fluorine, hydroxy, hydroxy-C₁₋₄-alkyl, C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₄-alkyl, C₁₋₄-alkyl, trifluoromethyl,C₁₋₄-alkyl-carbonylamino, hydroxycarbonyl and C₁₋₄-alkoxycarbonyl.

Particularly preferred meanings of the group L2 are selected fromfluorine, hydroxy, hydroxy-C₁₋₄-alkyl, C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₄-alkyl, C₁₋₄-alkyl, hydroxycarbonyl andC₁₋₄-alkoxy-carbonyl; particularly hydroxy, hydroxymethyl,methoxymethyl, methoxy, methyl, hydroxycarbonyl, methoxycarbonyl andethoxycarbonyl.

The group R⁶ preferably denotes according to the invention hydrogen,(C₁₋₈-alkyl)oxy-carbonyl, C₁₋₈-alkylcarbonyl or benzoyl, particularlyhydrogen or (C₁₋₆-alkyl)oxycarbonyl or C₁₋₆-alkylcarbonyl, particularlypreferably hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl,most particularly preferably hydrogen.

The substituents R^(7a), R^(7b), R^(7c) preferably representindependently of one another hydrogen, (C₁₋₈-alkyl)oxycarbonyl,(C₁₋₁₈-alkyl)carbonyl or benzoyl, particularly hydrogen,(C₁₋₆-alkyl)oxy-carbonyl or (C₁₋₈-alkyl)carbonyl, particularlypreferably hydrogen, methoxycarbonyl, ethoxy-carbonyl, methylcarbonyl orethylcarbonyl. Most particularly preferably R^(7a), R^(7b) and R^(7c)represent hydrogen.

The compounds of formula I wherein R⁶, R^(7a), R^(7b) and R^(7c)according to the invention have a meaning other than hydrogen, forexample C₁₋₈-alkylcarbonyl, are preferably suitable as intermediateproducts for the synthesis of compounds of formula I wherein R⁶, R^(7a),R^(7b) and R^(7c) denote hydrogen.

Particularly preferred compounds of general formula I are selected fromamong formulae I.2a to I.2L, particularly I.2b, I.2e, I.2h and I.2k;even more preferably I.2b and I.2e:

while the groups R¹ to R³ and R⁶ and R^(7a), R^(7b), R^(7c) have one ofthe meanings given previously, particularly have one of the givenmeanings specified as being preferred; and particularly

-   R¹ denotes fluorine, chlorine, bromine, cyano, C₁₋₄-alkyl,    C₁₋₄-alkyloxy, C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyloxy, while in a    C₅₋₆-cycloalkyl ring a methylene group may be replaced by O, and    wherein any alkyl group and cycloalkyl ring may be mono- or    poly-fluorinated and/or mono- or disubstituted with identical or    different substituents L2; even more preferably R¹ denotes chlorine,    bromine, methyl, ethyl, cyano, methoxy, ethoxy, cyclopropyl,    cyclobutyl; and-   R² denotes hydrogen, fluorine, methoxy, ethoxy or methyl,    particularly hydrogen; and-   R³ denotes chlorine, bromine, iodine, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,    hydroxyl, C₁₋₄-alkyloxy, C₃₋₇-cycloalkyloxy, C₁₋₄-alkylsulfanyl,    C₃₋₇-cycloalkylsulfanyl, while in a C₅₋₆-cycloalkyl ring a methylene    group may be replaced by O; and wherein any alkyl group and    cycloalkyl ring may be mono- or polyfluorinated and/or mono- or    disubstituted with identical or different substituents L2; even more    preferably R³ denotes chlorine, bromine, methyl, ethyl, propyl,    isopropyl, cyclopropyl, butyl, sec-butyl, iso-butyl, tert-butyl,    difluoromethyl, trifluoromethyl, 2-hydroxyl-ethyl, hydroxymethyl,    3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,    3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,    2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxyl, methoxy, ethoxy,    isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy,    cyclopentoxy, cyclohexyloxy, (S)-tetrahydrofuran-3-yloxy,    (R)-tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, methylsulfanyl    and ethylsulfanyl;-   L2 independently of one another are selected from among fluorine,    hydroxy, hydroxy-C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkyl,    C₁₋₄-alkyl, trifluoromethyl, C₁₋₄-alkyl-carbonylamino,    hydroxycarbonyl and C₁₋₄-alkyloxycarbonyl; particularly hydroxy,    hydroxymethyl, methoxymethyl, methoxy, methyl, hydroxycarbonyl,    methoxycarbonyl and ethoxycarbonyl; and-   R⁶ denotes hydrogen, (C₁₋₆-alkyl)oxycarbonyl, (C₁₋₆-alkyl)carbonyl    or benzoyl, particularly hydrogen, methylcarbonyl, methoxycarbonyl    or ethoxycarbonyl, most particularly preferably hydrogen; and-   R^(7a), R^(7b), R^(7c) independently of one another represent    hydrogen, (C₁₋₆-alkyl)oxycarbonyl, (C₁₋₈-alkyl)carbonyl or benzoyl,    particularly hydrogen, methoxycarbonyl, ethoxycarbonyl,    methylcarbonyl or ethylcarbonyl, particularly preferably hydrogen;    including the tautomers, the stereoisomers, the mixtures thereof and    the salts thereof.

The compounds of general formula I specified in the experimental sectionthat follows, and the derivatives thereof, wherein R⁶ has a meaningaccording to the invention other than hydrogen, particularly wherein R⁶denotes acetyl, ethoxycarbonyl or methoxycarbonyl, including thetautomers, the stereoisomers thereof and the mixtures thereof, arepreferred according to another variant of this invention.

In the processes according to the invention the groups R¹, R², and R³preferably have the meanings specified hereinbefore as being preferred.Moreover R′ preferably denotes H, C₁₋₃-alkyl or benzyl, particularly H,ethyl or methyl. The groups R^(8a), R^(8b), R^(8c) and R^(8d)independently of one another preferably denote H, C₁₋₄-alkylcarbonyl orbenzyl, particularly H, methylcarbonyl, ethylcarbonyl or benzyl.

The invention also relates to compounds of general formula IV

wherein Hal denotes chlorine, bromine or iodine and the groups R¹, R²and R³ are as hereinbefore defined, as intermediate products or startingmaterials in the synthesis of the compounds according to the invention.Particularly preferably, the groups R¹, R² and R³ have the meaningsgiven following formulae I.2a to I.2f.

The invention also relates to compounds of general formula II

wherein R′, R^(8a), R^(8b), R^(8c), R^(8d), R¹, R² and R³ are defined ashereinbefore and hereinafter; particularly wherein R′ denotes H,C₁₋₃-alkyl or benzyl, particularly H, ethyl or methyl; and the groupsR^(8a), R^(8b), R^(8c) and R^(8d) independently of one another representH, C₁₋₄-alkylcarbonyl, allyl or benzyl, particularly H, methylcarbonyl,ethylcarbonyl or benzyl and the groups R¹, R² and R³ are as hereinbeforedefined. These compounds may serve as intermediate products or startingmaterials in the synthesis of the compounds according to the invention.Particularly preferably the groups R¹, R² and R³ have the meanings givenfollowing formulae I.2a to I.2L.

Some terms used above and hereinafter to describe the compoundsaccording to the invention will now be defined more closely.

The term halogen denotes an atom selected from the group consisting ofF, Cl, Br and I, particularly F, Cl and Br.

The term C_(1-n)-alkyl, wherein n may have a value of 2 to 18, denotes asaturated, branched or unbranched hydrocarbon group with 1 to n C atoms.Examples of such groups include methyl, ethyl, n-propyl, iso-propyl,butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C_(2-n)-alkynyl, wherein n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a C≡Ctriple bond. Examples of such groups include ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl etc. Unless otherwise stated alkynyl groups are connected tothe remainder of the molecule via the C atom in position 1. Thereforeterms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent tothe terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc. This alsoapplies analogously to C_(2-n)-alkenyl groups.

The term C_(1-n)-alkoxy denotes a C_(1-n)-alkyl-O group, whereinC_(1-n)-alkyl is as hereinbefore defined. Examples of such groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy,tert-pentoxy, n-hexoxy, iso-hexoxy etc.

The term C_(1-n)-alkylcarbonyl denotes a C_(1-n)-alkyl-C(═O) group,wherein C_(1-n)-alkyl is as hereinbefore defined. Examples of suchgroups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl,n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C_(3-n)-cycloalkyl denotes a saturated mono-, bi-, tri- orspirocarbocyclic group with 3 to n C atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, decalinyl, bicyclo[3.2.1.]octyl,spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.Preferably the term C_(3-n)-cycloalkyl denotes saturated monocyclicgroups.

The term C_(5-n)-cycloalkenyl denotes a C_(5-n)-cycloalkyl group whichis as hereinbefore defined and additionally has at least one unsaturatedC═C double bond.

The term C_(3-n)-cycloalkylcarbonyl denotes a C_(3-n)-cycloalkyl-C(═O)group wherein C_(3-n)-cycloalkyl is as hereinbefore defined.

The term tri-(C₁₋₄-alkyl)silyl comprises silyl groups which haveidentical or two or three different alkyl groups.

The term di-(C₁₋₃-alkyl)amino comprises amino groups which haveidentical or two different C₁₋₃-alkyl groups.

The term aryl preferably denotes naphthyl or phenyl, more preferablyphenyl.

The term heteroaryl denotes a 5- or 6-membered monocyclic aromatic ringpossessing one to four identical or different heteroatoms selected fromthe group comprising N, O and S. Heteroaryl denotes preferably apyrrolyl, furanyl, thienyl, pyridyl or tetrazolyl group, or a pyrrolyl,furanyl, thienyl or pyridyl group wherein one or two methine groups arereplaced in each case by a nitrogen atom.

The nomenclature in structural formulas used above and hereinafter, inwhich a bond of a substituent of a cyclic group, as e.g. a phenyl ring,is shown towards the centre of the cyclic group, denotes, unlessotherwise stated, that this substituent may be bound to any freeposition of the cyclic group bearing an H atom.

The compounds according to the invention may be obtained using methodsof synthesis known in principle. Preferably the compounds are obtainedby the following methods according to the invention which are describedin more detail hereinafter.

The glucose derivatives of formula II according to the invention may besynthesised from D-gluconolactone or a derivative thereof by adding thedesired benzylbenzene compound in the form of an organometallic compound(Scheme 1).

The reaction according to Scheme 1 is preferably carried out startingfrom a halogenated benzylbenzene compound of general formula IV, whereinHal denotes chlorine, bromine, or iodine. The Grignard or lithiumreagent of benzylbenzene (V) may be prepared from the correspondingchlorinated, brominated or iodinated benzylbenzene IV either via aso-called halogen-metal exchange reaction or by inserting the metal intothe carbon-halogen bond. The halogen-metal exchange to synthesize thecorresponding lithium compound V may be carried out for example with anorganolithium compound such as e.g. n-, sec- or tert-butyllithium. Theanalogous magnesium compound may also be generated by a halogen-metalexchange with a suitable Grignard reagent such as e.g. isopropyl- orsec-butylmagnesium bromide or chloride or diisopropyl- ordi-sec-butylmagnesium without or in the presence of an additional saltsuch as e.g. lithium chloride that may accelerate the metalationprocess; the specific transmetalating organomagnesium compound may alsobe generated in situ from suitable precursors (see e.g. Angew. Chem.2004, 116, 3396-3399 and Angew. Chem. 2006, 118, 165-169 and referencesquoted therein). In addition, ate complexes of organomagnesium compoundsresulting from combining e.g. butylmagnesium chloride or bromide orisopropylmagnesium chloride or bromide and butyllithium, may be employedas well (see e.g. Angew. Chem. 2000, 112, 2594-2596 and TetrahedronLett. 2001, 42, 4841-4844 and references quoted therein). Thehalogen-metal exchange reactions are preferably carried out between 40°C. and −100° C., particularly preferably between 10° C. and −80° C., inan inert solvent or mixtures thereof, such as for example diethylether,dioxane, 1,2-dimethoxyethane, tetrahydrofuran, toluene, hexane,dimethylsulfoxide, dichloromethane or mixtures thereof. The magnesium orlithium derivatized compounds thus obtained may optionally betransmetalated with metal salts such as e.g. cerium trichloride, zincchloride or bromide, indium chloride or bromide, to form alternativeorganometal compounds (V) suitable for addition. Alternatively, theorganometal compound V may also be prepared by inserting a metal intothe carbon-halogen bond of the haloaromatic compound IV. Lithium ormagnesium are suitable elemental metals for this transformation. Theinsertion can be achieved in solvents such as e.g. diethylether,dioxane, 1,2-dimethoxyethane, tetrahydrofuran, toluene, hexane,dimethylsulfoxide and mixtures thereof at temperatures ranging from −80to 100° C., preferably at −70 to 40° C. In cases in which no spontaneousreaction takes place prior activation of the metal might be necessarysuch as e.g. treatment with 1,2-dibromoethane, iodine,trimethylsilylchloride, acetic acid, hydrochloric acid and/orsonication. The addition of the organometal compound V to gluconolactoneor derivatives thereof (VI) is preferably carried out at temperaturesbetween 40° C. and −100° C., particularly preferably at 0 to −80° C., inan inert solvent or mixtures thereof, to obtain the compound of formulaII. All foregoing reactions may be performed in air though executionunder inert gas atmosphere such as argon and nitrogen is preferred. Themetalation and/or coupling reaction may also be carried out inmicroreactors and/or micromixers which enable high exchange rates; forexample analogously to the processes described in WO 2004/076470.Suitable solvents for the addition of the metalated phenyl group V tothe appropriately protected gluconolactone VI are e.g. diethylether,dimethoxyethane, benzene, toluene, methylene chloride, hexane,tetrahydrofuran, dioxane, N-methylpyrrolidone and mixtures thereof. Theaddition reactions may be carried out without any further adjuvants orin the case of sluggishly reacting coupling partners in the presence ofa promoter such as e.g. BF₃*OEt₂ or Me₃SiCl (see M. Schlosser,Organometallics in Synthesis, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1994). Preferred definitions of thesubstituents R⁸ in Scheme 1 are benzyl, substituted benzyl, allyl,trialkylsilyl, particularly preferably trimethylsilyl,triisopropylsilyl, allyl, 4-methoxybenzyl and benzyl. If two adjacentsubstituents R⁸ are linked together, these two substituents arepreferably part of a benzylideneacetal, 4-methoxybenzylideneacetal,isopropylketal or constitute a dioxane with 2,3-dimethoxy-butylene whichis linked via the 2 and 3 positions of the butane with the adjacentoxygen atoms of the pyranose. The group R′ preferably denotes hydrogen,C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl or C₁₋₄-alkyloxycarbonyl, particularlypreferably hydrogen, methyl or ethyl. The group R′ is introduced afterthe addition of the organometallic compound V or a derivative thereof tothe gluconolactone VI. If R′ equals hydrogen or C₁₋₄-alkyl the reactionsolution is treated with an alcohol such as e.g. methanol or ethanol orwater in the presence of an acid such as e.g. acetic acid,methanesulfonic acid, toluenesulfonic acid, sulfuric acid,trifluoroacetic acid, or hydrochloric acid. R′ may also be attachedafter preparation of the hydrogen compound II. During installing R′ theprotective groups R⁸ may be cleaved if labile under the reactionconditions employed resulting in the corresponding protonated compound,i.e. compound II in which R⁸ equals H.

The synthesis of haloaromatic compound of formula IV may be carried outusing standard transformations in organic chemistry or at least methodsknown from the specialist literature in organic synthesis (see interalia J. March, Advanced Organic Reactions, Reactions, Mechanisms, andStructure, 4th Edition, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1992 and literature cited therein).More specifically, the use of transition metals and organo metalcompounds for the synthesis of aromatic compounds has been detailed indifferent monographs (see e.g. L. Brandsma, S. F. Vasilevsky, H. D.Verkruijsse, Application of Transition Metal Catalysts in OrganicSynthesis, Springer-Verlag, Berlin/Heidelberg, 1998; M. Schlosser,Organometallics in Synthesis, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1994; P. J. Stang, F. Diederich,Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 andreferences quoted therein). The synthesis strategies described in thefollowing provide a demonstration of this, by way of example. Inaddition, the aglycon part may also be assembled with the pyranosemoiety already present using the same synthetic approaches.

Scheme 2 shows the preparation of a precursor compound that may servefor the synthesis of the haloaromatic compound of formula IV startingfrom a benzoylchloride and a second aromatic group applyingFriedel-Crafts acylation conditions or variations thereof. This classicreaction has a wide substrate scope and is commonly carried out in thepresence of a catalyst which is used in catalytic or stoichiometricamounts, such as e.g. AlCl₃, FeCl₃, iodine, iron, ZnCl₂, sulphuric acid,or trifluoromethanesulphonic acid. Instead of the benzoyl chloride thecorresponding carboxylic acid, anhydride, ester or benzonitrile may beused as well. The reactions are preferentially carried out inchlorinated hydrocarbons such as e.g. dichloromethane and1,2-dichloroethane at temperatures from −30 to 120° C., preferably at 30to 100° C. However, solvent-free reactions or reactions in a microwaveoven are also possible.

In Scheme 3 the substituent R denotes C₁₋₃-alkyl or aryl. Starting fromthe diarylketone or diarylmethanol the diarylmethane is accessible inone or two reaction steps. The diarylketone may be reduced to thediarylmethane in two steps via the corresponding diphenylmethanol or inone step. In the two-step variant the ketone is reduced with a reducingagent such as for example a metal hydride such as e.g. NaBH₄, LiAlH₄ oriBu₂AlH to form the alcohol. The resulting alcohol can be converted inthe presence of a Lewis acid such as for example BF₃*OEt₂, InCl₃ orAlCl₃ or Brønsted acid such as for example hydrochloric acid, sulfuricacid, trifluoroacetic acid, or acetic acid with a reducing agent such ase.g. Et₃SiH, NaBH₄, or Ph₂SiClH to the desired diphenylmethane. Theone-step process starting from the ketone to obtain the diphenylmethanemay be carried out e.g. with a silane such as e.g. Et₃SiH, a borohydridesuch as e.g. NaBH₄ or an aluminum hydride such as LiAlH₄ in the presenceof a Lewis or Brønsted acid such as for example BF₃*OEt₂,tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid,aluminum chloride or InCl₃. The reactions are preferably carried out insolvents such as e.g. halogenated hydrocarbons such as dichloro-methane,toluene, acetonitrile, or mixtures thereof at temperatures of −30 to150° C., preferably at 20 to 100° C. Reductions with hydrogen in thepresence of a transition metal catalyst such as e.g. Pd on charcoal areanother possible method of synthesis. Reductions according toWolff-Kishner or variants thereof are also possible. The ketone isfirstly converted with hydrazine or a derivative thereof, such as e.g.1,2-bis(tert-butyldimethyl-silyl)hydrazine, into the hydrazone whichbreaks down under strongly basic reaction conditions and heating to formthe diphenylmethane and nitrogen. The reaction may be carried out in onereaction step or after isolation of the hydrazone or a derivativethereof in two separate reaction steps. Suitable bases include e.g. KOH,NaOH or KOtBu in solvents such as e.g. ethyleneglycol, toluene, DMSO,2-(2-butoxyethoxy)ethanol or tert-butanol; solvent-free reactions arealso possible. The reactions may be carried out at temperatures between20 to 250° C., preferably between 80 to 200° C. An alternative to thebasic conditions of the Wolff-Kishner reduction is the Clemmensenreduction which takes place under acidic conditions, which may also beused here. The alcohol function in diarylmethanol may also first betransformed into a better leaving group such as e.g. chloride, bromide,iodide, acetate, carbonate, phosphate, or sulfate; the subsequentreduction step to form the diarylmethane is widely described in theorganic chemistry literature.

In Scheme 4 the term “Alk” denotes C₁₋₃-alkyl and each substituent R isindependently selected from each other from the group consisting of H,C₁₋₃-alkyl and C₁₋₃-alkoxy. Scheme 4 delineates the synthesis ofdiarylmethanes and possible precursor compounds thereof starting from ametalated phenyl group. Lithium or magnesium substituted aromaticcompounds may be synthesized from chlorinated, brominated, or iodinatedaromatics by a halogen-metal exchange reaction with an organolithiumcompound such as e.g. n-, sec- or tert-butyllithium or a suitableGrignard reagent such as e.g. isopropyl- or sec-butylmagnesium bromideor chloride or diisopropyl- or di-sec-butylmagnesium without or in thepresence of an additional salt such as e.g. lithium chloride that mayaccelerate the metalation process; the specific transmetalatingorganomagnesium compound may also be generated in situ from suitableprecursors. In addition, ate complexes of organomagnesium compoundsresulting from combining e.g. butylmagnesium chloride or bromide orisopropylmagnesium chloride or bromide and butyllithium, may be employedas well. Insertion of the elemental metal into the halogen-carbon bondmight be also applicable. The corresponding boron substituted compoundsuch as e.g. boronic acid, boronic acid ester, or dialkylarylborane, isaccessible from these metalated phenyl groups by reaction with a boronelectrophile such as e.g. boronic acid ester or a derivative thereof. Inaddition, the borylated aromatic compound may also be prepared from thecorresponding halogenated or pseudohalogenated precursor and a diboronor borane compound through a transition metal, e.g. palladium, catalyzedreaction (see e.g. Tetrahedron Lett. 2003, p. 4895-4898 and referencesquoted therein). Alternatively, the lithium or magenesium derivatizedphenylmetal compounds may be accessed by replacement of a hydrogen atomusing a lithium or magnesium base. Employable bases may be e.g. n-, sec-or tert-butyllithium, butyl or i-propylmagnesium halide,2,2,6,6-tetramethylpiperidino lithium or magnesiumhalide, lithium ormagnesium diisopropylamide that may be used in combination withadditional salts such as e.g. lithium chloride or bases such as e.g.potassium t-butoxide (see e.g. Angew. Chem. 2006, 118, 3024-3027 andTetrahedron Lett. 2004, 45, 6697-6701 and references cited therein). Thelithium or magnesium substituted phenyl compounds add to benzaldehydes(step 3) and benzoic acids or derivatives thereof (step 4) such asbenzoic acid esters, benzamides such as e.g. of the Weinreb type,benzonitriles, or benzoyl chlorides. These reactions may principally beconducted without an additional transition metal catalyst ortransmetalation to another metal such as e.g. cerium, indium or zinc;sometimes the use of one of the latter alternatives is advantageous.Aryl boronic acids can be added to benzaldehydes by means of a rhodiumcatalyst furnishing the respective diarylmethanol (see e.g. Adv. Synth.Catal. 2001, p. 343-350 and references quoted therein). Moreover,arylboronic acids, esters thereof, dialkylarylboranes, oraryltrifluoroborates may be coupled with benzoyl chlorides mediated by atransition metal such as e.g. palladium, a complex or a salt thereofdelivering diarylketones. Metalated phenyl groups can be reacted withbenzyl electrophiles such as benzyl chlorides, bromides, or iodidesaffording diarylmethanes. Lithium or magnesium derivatized phenylcompounds are reacted favorably but not always necessarily in thepresence of a transition metal such as e.g. copper, iron, or palladium(see e.g. Org. Lett. 2001, 3, 2871-2874 and references quoted therein).Transmetallation from lithium or magnesium to e.g. boron, tin, silicon,or zinc furnishes e.g. the corresponding aromatic boronic acids,stannanes, silanes or zinc compounds, respectively, that may undergocoupling with benzyl electrophiles, e.g. benzyl halogenides, carbonates,phosphates, sulfonates, or carboxylic esters. The reaction is conductedin the presence of a transition metal, e.g. palladium, nickel, rhodium,copper, or iron (see e.g. Tetrahedron Lett. 2004, p. 8225-8228 and Org.Lett. 2005, p. 4875-4878 and references cited therein).

In order to prepare compounds of general formula I, in process a)according to the invention, a compound of general formula II

wherein R′, R¹ to R³ are as hereinbefore defined andR^(8a), R^(8b), R^(8c), R^(8d) are as hereinbefore defined andindependently of one another represent for example acetyl, pivaloyl,benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, allyl,benzyl or substituted benzyl or in each case two adjacent groups R^(8a),R^(8b), R^(8c), R^(8d) are combined a benzylideneacetal,diisopropylsilylideneketal or isopropylideneketal or a2,3-dimethoxy-butylene group which is linked via position 2 and 3 of thebutylene group to the oxygen atoms of the pyranose ring and forms withthem a substituted dioxane,which may be obtained as hereinbefore described, is reacted with areducing agent in the presence of a Lewis or Brønsted acid.

Suitable reducing agents for the reaction include for example silanes,such as triethyl-, tripropyl-, triisopropyl- or diphenylsilane, sodiumborohydride, sodium cyanoborohydride, zinc borohydride, boranes, lithiumaluminium hydride, diisobutylaluminium hydride or samarium iodide. Thereductions are carried out without or in the presence of a suitableBrønsted acid, such as e.g. hydrochloric acid, toluenesulphonic acid,trifluoroacetic acid or acetic acid, or Lewis acid, such as e.g. borontrifluoride etherate, trimethylsilyltriflate, titanium tetrachloride,tin tetrachloride, scandium triflate or zinc iodide. Depending on thereducing agent and the acid used the reaction may be carried out in asolvent, such as for example methylene chloride, chloroform,acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane,ethanol, water or mixtures thereof at temperatures between −60° C. and120° C. One particularly suitable combination of reagents consists forexample of triethylsilane and boron trifluoride etherate, which isconveniently used in acetonitrile or dichloromethane at temperatures of−60° C. and 60° C. Moreover, hydrogen may be used in the presence of atransition metal catalyst, such as e.g. palladium on charcoal or Raneynickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol,ethanol, water or acetic acid, for the transformation described.

Alternatively, in order to prepare compounds of general formula Iaccording to process b) according to the invention, in a compound ofgeneral formula III

wherein R¹ to R³ are as hereinbefore defined andR^(8a) to R^(d) denote one of the protective groups definedhereinbefore, such as e.g. an acyl, allyl, arylmethyl, acetal, ketal orsilyl group, and which may be obtained for example by reduction from thecompound of formula II as hereinbefore described, the protective groupsare cleaved.

Any acyl protecting group used is cleaved for example hydrolytically inan aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulfuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C. A trifluoroacetyl group ispreferably cleaved by treating with an acid such as hydrochloric acid,optionally in the presence of a solvent such as acetic acid attemperatures between 50 and 120° C. or by treating with sodium hydroxidesolution optionally in the presence of a solvent such as tetrahydrofuranor methanol at temperatures between 0 and 50° C.

Any acetal or ketal protecting group used is cleaved for examplehydrolytically in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulfuric acid or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

A trimethylsilyl group is cleaved for example in water, an aqueoussolvent mixture or a lower alcohol such as methanol or ethanol in thepresence of a base such as lithium hydroxide, sodium hydroxide,potassium carbonate or sodium methoxide.

In aqueous or alcoholic solvents, acids such as e.g. hydrochloric acid,trifluoroacetic acid or acetic acid are also suitable. For cleaving inorganic solvents, such as for example diethyl ether, tetrahydrofuran ordichloromethane, it is also suitable to use fluoride reagents, such ase.g. tetrabutylammonium fluoride.

A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageouslycleaved hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxane, methanol or diethylether.

In the reactions described hereinbefore, any reactive groups presentsuch as ethynyl, hydroxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for an ethynyl group may betrialkylsilyl such as e.g. trimethylsilyl and triisopropylsilyl ordialkyl-hydroxymethyl such as e.g. 2-hydroxyisoprop-2-yl.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be, forexample, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaricacid, succinic acid, lactic acid, citric acid, tartaric acid or maleicacid.

Moreover, the compounds obtained may be converted into mixtures, forexample 1:1 or 1:2 mixtures with amino acids, particularly withalpha-amino acids such as proline or phenylalanine, which may haveparticularly favourable properties such as a high crystallinity.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature, for example the methods described in WO98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO2004/080990, WO 2004/013118, WO 2004/052902, WO 2004/052903, WO2005/092877, WO 06/010557, WO 06/018150, WO 06/037537, WO 06/089872, WO2006/064033 and US application US 2003/0114390.

As already mentioned, the compounds of general formula I according tothe invention and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly an inhibitory effecton the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.

The biological properties of the new compounds may be investigated asfollows:

The ability of the substances to inhibit the SGLT-2 activity may bedemonstrated in a test set-up in which a CHO-KL cell line (ATCC No. CCL61) or alternatively an HEK293 cell line (ATCC No. CRL-1573), which isstably transfected with an expression vector pZeoSV (Invitrogen, EMBLaccession number L36849), which contains the cDNA for the codingsequence of the human sodium glucose cotransporter 2 (Genbank Acc.No.NM_(—)003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport¹⁴C-labelled alpha-methyl-glucopyranoside (14C-AMG, Amersham) into theinterior of the cell in sodium-dependent manner.

The SGLT-2 assay is carried out as follows:

CHO-hSGLT2 cells are cultivated in Ham's F12 Medium (BioWhittaker) with10% foetal calf serum and 250 μg/ml zeocin (Invitrogen), andHEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calfserum and 250 μg/ml zeocin (Invitrogen). The cells are detached from theculture flasks by washing twice with PBS and subsequently treating withtrypsin/EDTA. After the addition of cell culture medium the cells arecentrifuged, resuspended in culture medium and counted in a Casy cellcounter. Then 40,000 cells per well are seeded into a white, 96-wellplate coated with poly-D-lysine and incubated overnight at 37° C., 5%CO₂. The cells are washed twice with 250 μl of assay buffer (HanksBalanced Salt Solution, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mMMgSO₄ and 10 mM HEPES (pH7.4), 50 μg/ml of gentamycin). 250 μl of assaybuffer and 5 μl of test compound are then added to each well and theplate is incubated for a further 15 minutes in the incubator. 5 μl of10% DMSO are used as the negative control. The reaction is started byadding 5 μl of ¹⁴C-AMG (0.05 μCi) to each well. After 2 hours'incubation at 37° C., 5% CO₂, the cells are washed again with 250 μl ofPBS (20° C.) and then lysed by the addition of 25 μl of 0.1 N NaOH (5min. at 37° C.). 200 μl of MicroScint20 (Packard) are added to each welland incubation is continued for a further 20 min at 37° C. After thisincubation the radioactivity of the ¹⁴C-AMG absorbed is measured in aTopcount (Packard) using a ¹⁴C scintillation program.

To determine the selectivity with respect to human SGLT1 an analogoustest is set up in which the cDNA for hSGLT1 (Genbank Acc. No. NM000343)instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.

The compounds of general formula I according to the invention may forexample have EC50 values below 1000 nM, particularly below 200 nM, mostpreferably below 50 nM.

In view of their ability to inhibit the SGLT activity, the compoundsaccording to the invention and the corresponding pharmaceuticallyacceptable salts thereof are suitable for the treatment and/orpreventative treatment of all those conditions or diseases which may beaffected by the inhibition of the SGLT activity, particularly the SGLT-2activity. Therefore, compounds according to the invention areparticularly suitable for the prevention or treatment of diseases,particularly metabolic disorders, or conditions such as type 1 and type2 diabetes mellitus, complications of diabetes (such as e.g.retinopathy, nephropathy or neuropathies, diabetic foot, ulcers,macroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, edema and hyperuricaemia. These substances arealso suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The substances are alsosuitable for improving or restoring the functionality of pancreaticcells, and also of increasing the number and size of pancreatic betacells. The compounds according to the invention may also be used asdiuretics or antihypertensives and are suitable for the prevention andtreatment of acute renal failure.

By the administration of a compound according to the invention anabnormal accumulation of fat in the liver may be reduced or inhibited.Therefore according to another aspect of the present invention there isprovided a method for preventing, slowing, delaying or treating diseasesor conditions attributed to an abnormal accumulation of liver fat in apatient in need thereof characterized in that a compound or apharmaceutical composition according to the present invention isadministered. Diseases or conditions which are attributed to an abnormalaccumulation of liver fat are particularly selected from the groupconsisting of general fatty liver, non-alcoholic fatty liver (NAFL),non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fattyliver, diabetic fatty liver, alcoholic-induced fatty liver or toxicfatty liver.

In particular, the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of diabetes, particularly type 1 and type 2diabetes mellitus, and/or diabetic complications.

In addition compounds according to the invention are particularlysuitable for the prevention or treatment of overweight, obesity(including class I, class II and/or class III obesity), visceral obesityand/or abdominal obesity.

The dosage required to achieve the corresponding activity for treatmentor prevention usually depends on the compound which is to beadministered, the patient, the nature and gravity of the illness orcondition and the method and frequency of administration and is for thepatient's doctor to decide. Expediently, the dosage may be from 1 to 100mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg,preferably 1 to 100 mg, by oral route, in each case administered 1 to 4times a day. For this purpose, the compounds according to the inventionmay be formulated, optionally together with other active substances,together with one or more inert conventional carriers and/or diluents,e.g. with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxymethylcelluloseor fatty substances such as hard fat or suitable mixtures thereof, toproduce conventional galenic preparations such as plain or coatedtablets, capsules, powders, suspensions or suppositories.

The compounds according to the invention may also be used in conjunctionwith other active substances, particularly for the treatment and/orprevention of the diseases and conditions mentioned above. Other activesubstances which are suitable for such combinations include for examplethose which potentiate the therapeutic effect of an SGLT antagonistaccording to the invention with respect to one of the indicationsmentioned and/or which allow the dosage of an SGLT antagonist accordingto the invention to be reduced. Therapeutic agents which are suitablefor such a combination include, for example, antidiabetic agents such asmetformin, sulphonylureas (e.g. glibenclamide, tolbutamide,glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g.rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) andantagonists, PPAR-gamma/alpha modulators (e.g. KRP 297),alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIVinhibitors (e.g. LAF237, MK-431), alpha2-antagonists, insulin andinsulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.The list also includes inhibitors of protein tyrosinephosphatase 1,substances that affect deregulated glucose production in the liver, suchas e.g. inhibitors of glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptorantagonists and inhibitors of phosphoenol pyruvate carboxykinase,glycogen synthase kinase or pyruvate dehydrokinase, lipid loweringagents such as for example HMG-CoA-reductase inhibitors (e.g.simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate),nicotinic acid and the derivatives thereof, PPAR-alpha agonists,PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterolabsorption inhibitors such as, for example, ezetimibe, bile acid-bindingsubstances such as, for example, cholestyramine, inhibitors of ileacbile acid transport, HDL-raising compounds such as CETP inhibitors orABC1 regulators or active substances for treating obesity, such assibutramine or tetrahydrolipostatin, dexfenfluramine, axokine,antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists,MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such asSB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes.

The dosage for the combination partners mentioned above is usefully 1/5of the lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention or a physiologically acceptable saltof such a compound combined with at least one of the active substancesdescribed above as a combination partner, for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be affected by inhibiting thesodium-dependent glucose cotransporter SGLT. These are preferablymetabolic diseases, particularly one of the diseases or conditionslisted above, most particularly diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; while ifthey are used at staggered times the two active substances are given tothe patient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one of the active substances described above as combinationpartners, optionally together with one or more inert carriers and/ordiluents.

Thus, for example, a pharmaceutical composition according to theinvention comprises a combination of a compound of formula I accordingto the invention or a physiologically acceptable salt of such a compoundand at least one angiotensin II receptor antagonist optionally togetherwith one or more inert carriers and/or diluents.

The compound according to the invention, or a physiologically acceptablesalt thereof, and the additional active substance to be combinedtherewith may both be present together in one formulation, for example atablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

In the foregoing and following text, H atoms of hydroxyl groups are notexplicitly shown in every case in structural formulae. The term “ambienttemperature” means temperatures in the range from 20 to 25° C. TheExamples that follow are intended to illustrate the present inventionwithout restricting it:

Preparation of the Starting Compounds: Example I

4-Bromo-2-bromomethyl-1-chloro-benzene

N-bromosuccinimide (4.0 g) is slowly added to a solution of4-bromo-1-chloro-2-hydroxymethyl-benzene (5.0 g) and triphenylphosphine(5.9 g) in tetrahydrofuran (50 mL) chilled to 5° C. After 1 h stirringat ambient temperature the precipitate is filtered off, and the solventis removed in vacuo. The residue is purified by chromatography on silicagel (cyclohexane/ethyl acetate 50:1).

Yield: 4.9 g (76% of theory)

Mass spectrum (EI): m/z=282/284/286/288 (2Br+Cl) [M]⁺

Example II

4-Bromo-2-chloromethyl-1-chloro-benzene

A solution of 4-bromo-1-chloro-2-hydroxymethyl-benzene (40.0 g) andthionyl chloride (60 mL) in dichloromethane (150 mL) is stirred at45-50° C. for 5 h. Then the solvent and the excess reagent is removed invacuo.

Yield: 43.2 g (100% of theory)

Mass spectrum (EI): m/z=238/240/242/244 (Br+2Cl) [M]⁺

Example III

4-Bromo-1-chloro-2-phenoxymethyl-benzene

To a mixture of phenol (7.1 g) and potassium carbonate (11.1 g) inethanol (100 mL) is added 4-bromo-2-bromomethyl-1-chloro-benzene (19.5g). The mixture is stirred at ambient temperature over night. Theethanol is evaporated, and water is added to the residue. The resultingmixture is extracted with ethyl acetate, the combined extracts are driedover sodium sulfate, and the solvent is removed. The residue is purifiedby chromatography on silica gel (cyclohexane/ethyl acetate 70:30).

Yield: 16.8 g (82% of theory)

Mass spectrum (ESI⁺): m/z=296/298/300 (Br+Cl) [M]⁺

Example IV

1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene

A solution of 4-bromo-1-chloro-2-phenoxymethyl-benzene (14.40 g) in drytetrahydrofuran (120 mL) is cooled to −78° C. under argon. n-Butyllithium (33.5 mL of a 1.7 M solution in hexane) is slowly added to thecooled solution. The resulting solution is stirred for 45 min at −78° C.and then a −78° C.-cold solution of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (25.10 g, ca. 90%pure) in tetrahydrofuran (80 mL) is added through a transfer needle. Theresulting solution is stirred for 1 h at −78° C., and then aqueousacetic acid (150 mL of a 1% solution in water) is added. After warmingto room temperature, the resultant reaction mixture is extracted withethyl acetate, the combined organic extracts are washed with brine anddried over sodium sulfate. After removal of the solvent the residue isdissolved in methanol (90 mL) and treated with methanesulfonic acid (1mL). The solution is stirred at room temperature over night and thenneutralized with triethylamine. The solvent is removed under reducedpressure and the residue is dissolved in 250 mL ethyl acetate. Theorganic solution is washed with water and brine and dried over sodiumsulfate. After removal of the solvent, the crude product is submitted toreduction without further purification.

Yield: 17.20 g (crude product)

Mass spectrum (ESI⁺): m/z=433/435 (Cl) [M+Na]⁺

Example V

1-Chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene

A solution of1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene(17.20 g) and triethylsilane (13.6 mL) in dichloromethane (120 mL) andacetonitrile (360 mL) is cooled to −10° C. Then boron trifluorideetherate (8.4 mL) is added dropwise so that the solution temperaturemaintained below 0° C. The resultant solution is stirred for 0.5 h in anice bath and then warmed to room temperature. Aqueous sodium hydrogencarbonate solution is added, and the resulting mixture is stirred for0.5 h. The organic layer is separated and the aqueous layer is extractedwith ethyl acetate. The combined organic layers are washed with brineand dried over sodium sulfate. The solvent is removed, and the residueis taken up in dichloromethane (200 mL). The solution is cooled in anice-bath and pyridine (36 mL), acetic anhydride (40 mL) and4-dimethylaminopyridine (0.5 g) are added. The resultant solution isstirred for 1 h at ambient temperature and then diluted withdichloromethane (100 mL). The organic solution is washed twice withhydrochloric acid (1 mol/l in water) and dried over sodium sulfate.

Yield: 7.30 g (32% of theory)

Mass spectrum (ESI⁺): m/z=566/568 (Cl) [M+NH₄]⁺

Example VI

1-Chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene

To a solution of1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-phenyloxymethyl-benzene(6.04 g) in acetic acid (200 mL) is added hydrobromic acid (200 mL, 33%in acetic acid). The solution is stirred for 2 h at ambient temperatureand then cooled in an ice-bath. The reaction mixture is neutralized withchilled aqueous saturated potassium carbonate solution, and theresultant mixture is extracted with ethyl acetate. The combined organicextracts are dried over sodium sulfate, and the solvent is removed invacuo. The residue is taken up in ethyl aceate/cyclohexane (1:3), andthe precipitate is separated by filtration and dried at 50° C. to givethe pure product.

Yield: 4.50 g (76% of theory)

Mass spectrum (ESI⁺): m/z=552/554/556 (Br+Cl) [M+NH₄]⁺

Example VII

2-Chloro-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzaldehyde

To a solution of1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene(2.0 g) in acetonitrile (20 mL) is added N-methylmorpholine-N-oxide(0.47 g). The resulting solution is stirred at ambient temperature for 2h before more N-methylmorpholine-N-oxide (0.20 g) is added. Afterstirring at ambient temperature overnight, the solvent is removed underreduced pressure and the residue is filtered over silica gel elutingwith dichloromethane.

Yield: 1.21 g (69% of theory)

Mass spectrum (ESI⁺): m/z=488/490 (Cl) [M+NH₄]⁺

Example VIII

2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anisol

To a solution of 4-bromo-2,6-difluoro-anisol (3.0 g) in dry dioxane (50mL) and under argon atmosphere is added bis(pinacolato)diboron (5.13 g),potassium acetate (3.94 g), 1,1′-bis(diphenylphosphino)-ferrocene (0.55g) and 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium (II) (0.82g). The flask is tightly sealed and heated to 80° C. for 16 h. Then thereaction mixture is concentrated under reduced pressure and the residueis taken up in ethyl acetate. The resulting mixture is washed withwater, dried (sodium sulphate) and the solvent is evaporated. Theremainder is purified by chromatography on silica gel (cyclohexane/ethylacetate 1:0->2:1).

Yield: 0.88 g (24% of theory)

Mass spectrum (ESI⁺): m/z=271 [M+H]⁺

Example IX

2,6-Difluoro-4-methoxy-phenyl-boronic acid

To a solution of2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anisol (0.88g) in acetone (15 mL) is added aqueous ammonium acetate solution (18 mL,1 mol/L in water) and sodium metaiodate (2.6 g). Then the solution isstirred at ambient temperature overnight. Then the mixture isconcentrate, diluted with water and extracted with ethyl acetate. Thecombined extracts are dried (sodium sulfate) and the solvent is removedunder reduced pressure. The residue is purified by chromatography onsilica gel (cyclohexane/ethyl acetate 1:0->1:1).

Yield: 0.27 g (44% of theory)

Example X

1-Chloro-2-[2,3-difluoro-4-methyl-phenyl)methyl]-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene

Pyridine (0.11 g), acetic anhydride (0.14 g) and 4-dimethylaminopyridine(0.10 g) are added to a solution of1-chloro-2-[2,3-difluoro-4-methyl-phenyl)methyl]-4-(D-glucopyranos-1-yl)-benzene(0.11 g) in dichloromethane (3 mL). The resultant solution is stirredfor 3 h at ambient temperature and then diluted with dichloromethane.The organic solution is washed twice with hydrochloric acid (1 mol/l inwater), dried (sodium sulphate) and concentrated under reduced pressureto give the product.

Yield: 0.15 g (97% of theory)

Preparation of the End Compounds: Example 1

1-Chloro-2-[2,3-difluoro-4-methyl-phenyl)methyl]-4-(D-glucopyranos-1-yl)-benzene

A solution of 2,3-difluoro-toluene (0.82 g) in dry tetrahydrofuran (13mL) is cooled to −80° C. under argon. sec-Butyl lithium (4.55 mL of a1.4 M solution in cyclohexane) is slowly added to the cooled solutionand the resulting solution is stirred for 2 h at −80° C. Then a solutionof 2-chloro-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzaldehyde(0.30 g) in tetrahydrofuran (3 mL) is added and the resulting solutionis stirred for another 0.5 h at −80° C. The reaction is quenched by theaddition of aqueous ammonium chloride solution and warmed to roomtemperature. The resultant mixture is extracted with ethyl acetate, thecombined organic extracts are washed with brine and dried over sodiumsulfate. After removal of the solvent, the residue is taken up indichloromethane (6 mL) and the resulting solution is cooled in anice-bath. Triethylsilane (0.7 mL) followed by boron trifluoride etherate(0.38 mL) is added and the reaction solution is stirred at ambienttemperature for 3 h. Aqueous sodium bicarbonate solution is added andthe resulting mixture is extracted with ethyl acetate. The combinedextracts are dried (sodium sulfate) and the solvent is removed underreduced pressure. The residue is dissolved in methanol (10 mL) andtreated with aqueous potassium hydroxide solution (1 mL, 4 mol/L). Thesolution is stirred at room temperature for 30 min and neutralized withhydrochloric acid (1 mol/L). After removal of the methanol, the residueis diluted with aqueous sodium bicarbonate solution and the resultingmixture is extracted with ethyl acetate. The combined organic extractsare dried (sodium sulphate) and the solvent is evaporated. The remainderis purified by chromatography on silica gel (dichloromethane/methanol1:0->9:1).

Yield: 0.16 g (57% of theory)

Mass spectrum (ESI⁺): m/z=432/434 (Cl) [M+NH₄]⁺

The following compound may be obtained analogously to Example 1:

(2)1-Chloro-2-[(4-2,3-difluoro-ethyl-phenyl)-methyl]-4-(β-D-glucopyranos-1-yl)-benzene

Mass spectrum (ESI⁺): m/z=446/448 (Cl) [M+NH₄]⁺

The compound is prepared starting with 3-ethyl-1,2-difluoro-benzenewhich is synthesized from 2,3-difluoro-acetophenone by hydrogenationwith 10% palladium on carbon in the presence of concentratedhydrochloric acid in ethanol.

(3)1-Chloro-2-[(2,6-difluoro-4-methoxy-phenyl)-methyl]-4-(β-D-glucopyranos-1-yl)-benzene

Mass spectrum (ESI): m/z=496/498 (Cl) [M]⁺

The compound is prepared using 4-bromo-3,5-difluoro-anisol and n-butyllithium to generate the intermediate 2,6-difluoro-4-methoxy-phenyllithium via halogen-metal exchange. All subsequent steps are carried outas described above.

(4)1-Chloro-2-[(2,5-difluoro-4-methoxy-phenyl)-methyl]-4-(β-D-glucopyranos-1-yl)-benzene

The compound is prepared using 4-bromo-2,5-difluoro-anisol and n-butyllithium to generate the intermediate 2,5-difluoro-4-methoxy-phenyllithium via halogen-metal exchange. All subsequent steps are carried outas described above.

Example 5

1-Chloro-2-[(3,5-difluoro-4-methoxy-phenyl)-methyl]-4-(β-D-glucopyranos-1-yl)-benzene

A stirred mixture of1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene(0.30 g), 3,5-difluoro-4-methoxy-phenylboronic acid (0.21 g) andpotassium carbonate (0.31 g) in acetone (3 mL) and water (1 mL) underargon is cooled in an ice-bath. Then palladium dichloride (5 mg) isadded and the cooling bath is removed. The reaction mixture is stirredat ambient temperature overnight. Then brine is added and the resultingmixture is extracted with ethyl acetate. The combined extracts are driedover sodium sulfate, and the solvent is removed in vacuo. The residue istaken up in methanol (5 mL) aqueous potassium hydroxide solution (1 mL,4 mol/L) is added. The solution is stirred at ambient temperature for0.5 h and then neutralized with 1 M hydrochloric acid. The methanol isevaporated, and the residue is diluted with brine and extracted withethyl acetate. The organic extracts are dried over sodium sulfate, andthe solvent is removed. The residue is chromatographed on silica gel(dichloromethane/methanol 1:0->9:1).

Yield: 0.06 g (25% of theory)

Mass spectrum (ESI⁺): m/z=448/450 (Cl) [M+NH₄]⁺

Example 6

3-[2,3-difluoro-4-methyl-phenyl)methyl]-1-(D-glucopyranos-1-yl)-4-methyl-benzene

Toluene (3 mL) is added to a flask charged with1-chloro-2-[2,3-difluoro-4-methyl-phenyl)methyl]-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene(0.15 g), methylboronic acid (35 mg), K₃PO₄*H₂O (0.16 g),2-dicyclohexylphospino-2′,6′-dimethoxybiphenyl (8 mg) andpalladium(II)-acetate (2.2 mg) under argon atmosphere. The mixture isstirred at 115° C. overnight before another portion of methylboronicacid (35 mg), K₃PO₄*H₂O (0.16 g),2-dicyclohexylphospino-2′,6′-dimethoxybiphenyl (8 mg) andpalladium(II)-acetate (2.2 mg) is added. The mixture is stirred at 115°C. for another 16 h and then cooled to room temperature. Water is addedand the resulting mixture is extracted with ethyl acetate. The combinedextracts are dried (sodium sulfate) and the solvent is removed underreduced pressure. The residue is dissolved in methanol (4 mL) andtreated with aqueous potassium hydroxide solution (2 mL, 4 mol/L). Thesolution is stirred at room temperature for 30 min and then neutralizedwith hydrochloric acid (1 mol/L). After removal of the methanol, theresidue is diluted with aqueous sodium bicarbonate solution and theresulting mixture is extracted with ethyl acetate. The combined organicextracts are dried (sodium sulphate) and the solvent is evaporated. Theremainder is purified by HPLC on reversed phase (YMC C18,acetonitrile/water) to give the pure product.

Yield: 60 mg (59% of theory)

Mass spectrum (ESI⁺): m/z=412 [M+NH₄]⁺

The following compounds are also prepared analogously to theabove-mentioned Examples and other methods known from the literature:

Ex. Structure 7

8

9

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11

12

13

14

15

16

17

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21

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36

Some examples of formulations will now be described in which the term“active substance” denotes one or more compounds according to theinvention, including the salts thereof. In the case of one of thecombinations with one or additional active substances as describedpreviously, the term “active substance” also includes the additionalactive substances.

Example A Tablets Containing 100 mg of Active Substance Composition:

1 tablet contains:

active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mgpolyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

Example B Tablets Containing 150 mg of Active Substance Composition:

1 tablet contains:

active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate1.0 mg 300.0 mg

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

Example C Hard Gelatine Capsules Containing 150 mg of Active SubstanceComposition:

1 capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose(powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

Example D Suppositories Containing 150 mg of Active SubstanceComposition:

1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2,000.0 mg

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

Example E Ampoules Containing 10 mg Active Substance Composition:

active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilledwater ad 2.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

Example F Ampoules Containing 50 mg of Active Substance Composition:

4 active substance 50.0 mg 0.01 N hydrochloric acid q.s.double-distilled water ad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

1. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives ofgeneral formula I

wherein R¹ denotes hydrogen, fluorine, chlorine, bromine, iodine,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy, C₃₋₇-cycloalkyloxy,C₅₋₇-cycloalkenyloxy, C₁₋₄-alkylsulfanyl, amino, nitro or cyano, whilethe above-mentioned alkyl-, alkenyl-, alkynyl-, cycloalkyl- undcycloalkenyl-residues may be mono- or polysubstituted by fluorine and/ormono- or disubstituted by identical or different substituents L2, andwhile in the above-mentioned C₅₋₆-cycloalkyl and C₅₋₆-cycloalkenyl ringsone or two methylene groups may be replaced independently of one anotherby O, S, CO, SO or SO₂, and R² denotes hydrogen, fluorine, chlorine,bromine, hydroxy, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy or cyano, while the alkyl or alkoxy group may bemono- or polysubstituted by fluorine, and R³ hydrogen, fluorine,chlorine, bromine, iodine, C₁₋₆-alkyl, C₂₋₆-alkynyl, C₂₋₆-alkenyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₅₋₇-cycloalkenyl,C₅₋₇-cycloalkenyl-C₁₋₃-alkyl, aryl, heteroaryl, C₁₋₄-alkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)aminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,piperazin-1-ylcarbonyl, 4-(C₁₋₄-alkyl)piperazin-1-ylcarbonyl,hydroxycarbonyl, C₁₋₄-alkoxycarbonyl, C₁₋₄-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, piperidin-1′-yl, morpholin-4-yl,piperazin-1-yl, 4-(C₁₋₄-alkyl)piperazin-1-yl, C₁₋₄-alkylcarbonylamino,arylcarbonylamino, heteroarylcarbonylamino, C₁₋₄-alkylsulfonylamino,arylsulfonylamino, C₁₋₆-alkoxy, C₃₋₇-cycloalkyloxy,C₅₋₇-cycloalkenyloxy, aryloxy, heteroaryloxy, C₁₋₄-alkylsulfanyl,C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl, C₃₋₇-cycloalkylsulfanyl,C₃₋₇-cycloalkylsulfinyl, C₃₋₇-cycloalkylsulfonyl,C₅₋₇-cycloalkenylsulfanyl, C₅₋₇-cycloalkenylsulfinyl,C₅₋₇-cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl,heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, amino,hydroxy, cyano and nitro, while the above-mentioned alkyl-, alkenyl-,alkynyl-, cycloalkyl- und cycloalkenyl-residues may be mono- orpolysubstituted by fluorine and/or mono- or disubstituted by identicalor different substituents L2, and while in the above-mentionedC₅₋₆-cycloalkyl and C₅₋₆-cycloalkenyl rings one or two methylene groupsmay be replaced independently of one another by O, S, CO, SO or SO₂, andwhile in the above-mentioned N-heterocycloalkyl rings one methylenegroup may be replaced by CO or SO₂, and L1 independently of one anotherare selected from among fluorine, chlorine, bromine, iodine, hydroxy,cyano, C₁₋₃-alkyl, difluoromethyl, trifluoromethyl, C₁₋₃-alkoxy,difluoromethoxy, trifluoromethoxy, amino, C₁₋₃-alkyl-amino anddi(C₁₋₃-alkyl)-amino; and L2 independently of one another are selectedfrom among fluorine, chlorine, hydroxy, hydroxyl-C₁₋₄-alkyl,C₁₋₄-alkoxy, trifluoromethoxy, C₁₋₄-alkoxy-C₁₋₄-alkyl, cyano,hydroxycarbonyl, (C₁₋₄-alkyl)oxycarbonyl, aminocarbonyl, C₁₋₄-alkyl,trifluoromethyl, amino, C₁₋₄-alkyl-carbonylamino, C₁₋₃-alkyl-amino anddi(C₁₋₃-alkyl)-amino; and R⁶, R^(7a), R^(7b), R^(7c) independently ofone another have a meaning selected from among hydrogen,(C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl andaryl-(C₁₋₃-alkyl)-carbonyl, while the aryl-groups may be mono- ordisubstituted independently of one another by identical or differentgroups L1; while by the aryl groups mentioned in the definition of theabove groups are meant phenyl or naphthyl groups which may besubstituted as defined; and while, unless otherwise stated, theabove-mentioned alkyl groups may be straight-chain or branched,including tautomers, stereoisomers thereof or mixtures thereof, andphysiologically acceptable salts thereof.
 2. Glucopyranosyl-substituteddifluorobenzyl-benzene derivatives according to claim 1 characterized inthat R¹ denotes fluorine, chlorine, bromine, cyano, C₁₋₄-alkyl,C₁₋₄-alkyloxy, C₃₋₇-cycloalkyl or C₃₋₇-cycloalkyloxy, while in aC₅₋₆-cycloalkyl ring a methylene group may be replaced by 0, and whereinany alkyl group or cycloalkyl ring may be mono- or poly-fluorinatedand/or mono- or disubstituted with identical or different substituentsL2, wherein L2 is defined as in claim
 1. 3. Glucopyranosyl-substituteddifluorobenzyl-benzene derivatives according to claim 1 characterized inthat R² denotes hydrogen, fluorine, chlorine, methyl, methoxy, ethoxyand methyl substituted by 1 to 3 fluorine atoms. 4.Glucopyranosyl-substituted difluorobenzyl-benzene derivatives accordingto claim 1 characterized in that R³ denotes chlorine, bromine, iodine,C₁₋₄-alkyl, C₃₋₇-cycloalkyl, hydroxyl, C₁₋₄-alkyloxy,C₃₋₇-cycloalkyloxy, C₁₋₄-alkylsulfanyl, C₃₋₇-cycloalkylsulfanyl, whilein a C₅₋₆-cycloalkyl ring a methylene group may be replaced by O, andwherein any alkyl group and cycloalkyl ring may be mono- orpolyfluorinated and/or mono- or disubstituted with identical ordifferent substituents L2, wherein L2 is defined as in claim
 1. 5.Glucopyranosyl-substituted difluorobenzyl-benzene derivatives accordingclaim 1 characterized in that R⁶ denotes hydrogen,(C₁₋₈-alkyl)oxycarbonyl, C₁₋₈-alkylcarbonyl or benzoyl and R^(7a),R^(7b), R^(7c) represent independently of one another hydrogen,(C₁₋₈-alkyl)oxycarbonyl, (C₁₋₈-alkyl)carbonyl or benzoyl. 6.Glucopyranosyl-substituted difluorobenzyl-benzene derivatives accordingto claim 1 characterized in that R⁶, R^(7a), R^(7b), R^(7c) representhydrogen.
 7. Physiologically acceptable salts of the compounds accordingto claim 1 with inorganic or organic acids.
 8. Pharmaceuticalcomposition, comprising a compound according to claim 1 or aphysiologically acceptable salt thereof, optionally together with one ormore inert carriers and/or diluents.
 9. Method for the treatment orprevention of diseases or conditions which can be influenced byinhibiting the sodium-dependent glucose cotransporter SGLT comprisingadministering to a patient a compound according to claim 1 or aphysiologically acceptable salt thereof.
 10. Method for the treatment orprevention of one or more metabolic disorders comprising administeringto a patient a compound according to claim 1 or a physiologicallyacceptable salt thereof.
 11. Method according to claim 10, characterisedin that the metabolic disorder is selected from the group consisting oftype 1 and type 2 diabetes mellitus, complications of diabetes,metabolic acidosis or ketosis, reactive hypoglycaemia,hyperinsulinaemia, glucose metabolic disorder, insulin resistance,metabolic syndrome, dyslipidaemias of different origins, atherosclerosisand related diseases, obesity, high blood pressure, chronic heartfailure, oedema and hyperuricaemia.
 12. Method for inhibiting thesodium-dependent glucose cotransporter SGLT2 comprising administering toa patient a compound according to claim 1 or a physiologicallyacceptable salt thereof.
 13. Method for preventing the degeneration ofpancreatic beta cells and/or for improving and/or restoring thefunctionality of pancreatic beta cells comprising administering to apatient a compound according to claim 1 or a physiologically acceptablesalt thereof.
 14. Method for preventing, slowing, delaying or treatingdiseases or conditions attributed to an abnormal accumulation of liverfat in a patient in need thereof comprising administering to a patient acompound according to claim 1 or a physiologically acceptable saltthereof.
 15. Method for preparing a diuretic and/or antihypertensive.16. Process for preparing a compound according to claim 1, characterisedin that a) a compound of general formula II

wherein R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C₁₋₃-alkyl)-carbonyl,wherein the alkyl or aryl groups may be mono- or polysubstituted byhalogen; R^(8a), R^(8b), R^(8c), R^(8d) independently of one anotherhave one of the meanings given hereinbefore and hereinafter for thegroups R⁶, R^(7a), R^(7b), R^(7c), or denote a benzyl or allyl group ora R^(a)R^(b)R^(c)Si group or a ketal or acetal group, particularly analkylidene or arylalkylidene ketal or acetal group, while in each casetwo adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclicsilyl ketal, ketal or acetal group or a1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge, while theabove-mentioned ethylene bridge forms, together with two oxygen atomsand the two associated carbon atoms of the pyranose ring, a substituteddioxane ring, particularly a2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and while alkyl, aryland/or benzyl groups may be mono- or polysubstituted by halogen orC₁₋₃-alkoxy, and while benzyl groups may also be substituted by adi-(C₁₋₃-alkyl)amino group; and R^(a), R^(b), R^(c) independently of oneanother denote C₁₋₄-alkyl, aryl or aryl-C₁₋₃-alkyl, wherein the aryl oralkyl groups may be mono- or polysubstituted by halogen; while by thearyl groups mentioned in the definition of the above groups are meantphenyl or naphthyl groups, preferably phenyl groups; and wherein thegroups R¹ to R³ and R⁶, R^(7a), R^(7b), R^(7c) are defined as in claim1; is reacted with a reducing agent in the presence of a Lewis orBrønsted acid, while any protective groups present are cleavedsimultaneously or subsequently; or b) a compound of general formula III

wherein R^(8a), R^(8b), R^(8c), R^(8d) and R¹ to R³ are defined ashereinbefore and hereinafter, but at least one of the groups R^(8a),R^(8b), R^(8c), R^(8d) does not denote hydrogen, is hydrolysed to yielda compound of the formula I defined as in claim 1 wherein R⁶, R^(7a),R^(7b) and R^(7c) denote hydrogen, and if desired a compound of formulaI thus obtained wherein R⁶ denotes a hydrogen atom, is converted byacylation into a corresponding acyl compound of general formula I,and/or if necessary any protective group used in the reactions describedabove is cleaved and/or if desired a compound of formula I thus obtainedis resolved into its stereoisomers and/or if desired a compound offormula I thus obtained is converted into the salts thereof.
 17. Processfor preparing compounds of general formula II

wherein R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C₁₋₃-alkyl)-carbonyl,wherein the alkyl or aryl groups may be mono- or polysubstituted byhalogen; R^(8a), R^(8b), R^(8c), R^(8d) independently of one another hasone of the meanings given for the groups R⁶, R^(7a), R^(7b), R^(7c), ordenote a benzyl or allyl group or a R^(a)R^(b)R^(c)Si group or a ketalor acetal group, while in each case two adjacent groups R^(8a), R^(8b),R^(8c), R^(8d) may form a cyclic silyl ketal, ketal or acetal group ormay form, with two oxygen atoms of the pyranose ring, a substituted2,3-oxydioxane ring, particularly a2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and while alkyl, aryland/or benzyl groups may be mono- or polysubstituted by halogen orC₁₋₃-alkoxy, and while benzyl groups may also be substituted by adi-(C₁₋₃-alkyl)amino group; and R^(a), R^(b), R^(c) independently of oneanother denote C₁₋₄-alkyl, aryl or aryl-C₁₋₃-alkyl, while the alkyl oraryl groups may be mono- or polysubstituted by halogen; while by thearyl groups mentioned in the definition of the above groups are meantphenyl or naphthyl groups, preferably phenyl groups; and R¹ to R³, R⁶,R^(7a), R^(7b), R^(7c) are defined as in claim 1, wherein anorganometallic compound (V) which may be obtained by halogen-metalexchange or by inserting a metal in the carbon-halogen bond of ahalogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R¹ to R³ are defined as in claim 1,and optionally subsequent transmetallation, is added to a gluconolactoneof general formula VI

wherein R^(8a), R^(8b), R^(8c), R^(8d) are defined as in claim 1, andthen the resulting adduct is reacted with water or an alcohol R′—OH,while R′ denotes optionally substituted C₁₋₄-alkyl, in the presence ofan acid and optionally the product obtained in the reaction with waterwherein R′ denotes H is converted, in a subsequent reaction, with anacylating agent into the product of formula II wherein R′ denotes(C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl oraryl-(C₁₋₃-alkyl)-carbonyl, which may be substituted as specified.